Therapeutics for Rare and Neglected Diseases (TRND) · 2012. 8. 9. · The Problem of Rare and Neglected Diseases • ~7,000 diseases affect humankind – but only a small fraction

$Page 1: Therapeutics for Rare and Neglected Diseases (TRND) · 2012. 8. 9. · The Problem of Rare and Neglected Diseases • ~7,000 diseases affect humankind – but only a small fraction$
John McKew, PhD

Chief, Therapeutics Development Branch Division of Preclinical Innovation

TRND Road Show

Therapeutics for Rare and Neglected

Diseases (TRND)

Overview

• What is TRND?

• How to Apply to TRND

• TRND Evaluation Criteria

• TRND Project Selection and Agreements

• Questions

Overview

• What is TRND?




• Questions

What is TRND?

• An effort to speed development of new drugs for rare and neglected diseases

• A resource to help advance rare and neglected disease drug discovery projects from academia or industry

• An integral part of the NIH Director’s mandate to increase translational research within the NIH

Benefits for the Applicant

• Significant in-kind research to move your project forward

• Collaboration with TRND’s experienced group of drug discovery professionals to achieve your project goals

• Access to the broad scientific, clinical, and translational expertise within the NIH

The Problem of Rare and Neglected Diseases

• ~7,000 diseases affect humankind – but only a small fraction support commercial development of therapeutic agents

• Two types of neglected diseases:

– Low prevalence, i.e., “rare” (<200,000 prevalence in U.S.)

• There are >6000 rare (orphan) diseases

• Cumulative prevalence in U.S. ~ 25 – 30 million

• Most are single gene diseases

• <200 have any pharmacotherapy available

– High prevalence but “neglected”

• Occur chiefly among impoverished and marginalized

populations in developing nations (treatment costs

prohibitive)

• Most are infectious

Preclinical Development/TRND

FDA Collaboration

Paradigm/Technology Development

Repurposing

Lead

Optimization Preclinical

Development Probe/Lead

Development Target

Validation Target FDA

approval Clinical Trials

I II III

Project Entry Point

Repurposing

Unvalidated target

Validated target

Lead compound

Preclinical development

candidate

Clinical development

candidate

Assay Dev

Target assay

TRND Project Entree

• Small Molecule and Biologic modalities accepted

• Projects enter TRND from lead optimization to IND filing • After HTS and other lead finding and validation work is completed

TRND Features • NIH Intramural Drug Development Experts Partnering

with External Disease and Target Collaborators

– Partners can be Government, Academics, Non-Profit Foundations, Biotechnology and Pharmaceutical companies, ex-US groups

• Distinguishing features

– Collaboration / Partnerships (not service center)

– Entrepreneurial culture, fast decision-making

– Building laboratory and expertise infrastructure at NIH

– Disease agnostic, exploiting cross-cutting mechanisms

– Science of preclinical drug development

– Technology/paradigm development

• 20% of effort toward improving success rates

TRND Features: R&D Capabilities

• Drug project-specific activities

– New indications for clinical stage drugs and repurposing approved drugs

– Medicinal chemistry

– Rare disease bioassay development

– Efficacy, pharmacology, ADME, toxicology, PK/PD

– Compound scale-up, formulation

– Clinical and regulatory development strategy,

natural history studies assessments

– First in human clinical trials as needed

TRND Program Timeline

• FY09: Infrastructure (May 2009)

• FY10: Infrastructure and Pilot Projects (June 2010)

– Budget $24M

– Governance, hiring, research community outreach, pilot projects

• FY11: Infrastructure and Project Solicitation

– Budget $24M

– Sept 2010 solicitation yielded 4 projects; work began May 2011

– April 2011 solicitation yielded 6 projects; work began Sept 2011

• FY12: Maturing program within NCATS

– Budget $24M

– Current projects reviewed regularly to assess progress

– Aug – Sept 2012 solicitation; expect to select 3-5 projects

• 14 projects through pilot phase & 2 public solicitations since 2009

• Mix of small molecules and biologics

• Two innovative platform technologies

• 2 investigational drugs taken into humans

• CLL: IND filed with US FDA July 12th, approved Aug 5th 2011

• Phase I trial commenced September 2011

• SCD: IND filed Oct 14th 2011, approved Nov 10th 2011

• Phase I trial commenced December 2011

• Initiated first natural history study

• HIBM: NIH Clinical Center, 1st patient enrolled September 2011

• Every project is a unique Public-Private partnership

• Many include foundation and patient advocacy input

TRND Highlights

Active TRND Projects Collaborator Organization Name(s) Partner Type(s) Agent Therapeutic Area / Disease

TRND Pilot Project NPC-SOAR, Washington Univ., Einstein

College of Medicine, NICHD, NHGRI

Disease Foundation,

Academic, DIR

Repurposed

Approved Drug Niemann-Pick C

TRND Pilot Project New Zealand Pharmaceuticals, NHGRI Biotech, DIR Intermediate

Replacement

Hereditary Inclusion Body

Myopathy

TRND Pilot Project Aes-Rx, NHLBI Biotech, DIR NME Sickle Cell Disease

TRND Pilot Project Leukemia & Lymphoma Society, Kansas

Univ. Cancer Center

Disease Foundation,

Academic

Repurposed

Approved Drug

Chronic Lymphocytic

Leukemia

Reeves, Erica ReveraGen BioPharma Small Business NME Duchenne Muscular Dystrophy

Campbell, David Afraxis, Inc. Small Business NME Fragile X Syndrome

Garvey, Edward Viamet Pharmaceuticals, Inc. Small Business NME Cryptococcal Meningitis

Liu, Paul NHGRI DIR Repurposed

Approved Drug Core Binding Factor Leukemia

Kimberlin, David University of Alabama Academic Nucleotide

Analog Pro-drug Neonatal Herpes Simplex

Trapnell, Bruce Cincinnati Children’s Hospital Academic Biologic Autoimmune Pulmonary

Alveolar Proteinosis

Bloch, Kenneth Massachusetts General Hospital Academic NME Fibrodysplasia Ossificans

Progressiva

Liu, Julie CoNCERT Pharmaceuticals Small Business NME Schistosomiasis

Davis, Robert Lumos Pharma Small Business NME Creatine Transporter Defect

Sazani, Peter AVI BioPharma, Inc. Small Business Oligo (PMO) Duchenne Muscular Dystrophy

TRND Portfolio




Disease Foundation,

Academic, DIR

Repurposed



Replacement


Myopathy



Univ. Cancer Center

Disease Foundation,

Academic

Repurposed

Approved Drug

Chronic Lymphocytic

Leukemia











Progressiva




TRND Portfolio Active TRND Projects

Collaborator Organization Name(s) Partner Type(s) Agent Therapeutic Area / Disease



Disease Foundation,

Academic, DIR

Repurposed



Replacement


Myopathy



Univ. Cancer Center

Disease Foundation,

Academic

Repurposed

Approved Drug

Chronic Lymphocytic

Leukemia











Progressiva




Screening Derived Repurposing: How quickly can we take an approved drug and use it in a new patient population?

The

Learning

Collaborative™

• Focus on rare and neglected

diseases

• Industrial scale HTS,

medicinal chemistry, and

bioinformatics capabilities

• Pharma experience

• Bench to bedside translation

in drug repurposing

• National leadership in

medicinal and pharmaceutical

chemistry


• ~ 400 active research projects

• World-wide network of blood cancer experts

• Track record of commercial partnerships


The Learning Collaborative Capitalizing on Strengths

Clinical trial sites: KU (Bhalla) NIH (Wiestner) OSU (Byrd)

CLL ─ Chronic Lymphocytic Leukemia

• 30% of all leukemias

• Progresses more slowly than other types of leukemia; 80% of patients are over age 60

• ~15,000 new diagnoses/year in US

• Standard of Care: chemotherapy (fludarabine et al) and/or anti-CD20 mab (Rituxan)

• New treatments needed for refractory CLL patients

Overview of CLL screen

• Normal B-cells and CLL cells obtained from patients at NIH Clinical Center

• Adrian Wiestner, NHLBI

• Patient samples sent frozen to the NCGC (fresh samples also tested with similar results)

• Cells from six CLL patients and five normal donors tested

• NCGC Pharmaceutical Collection screened at 9 concentrations, 1 nM to 57 uM (1:5

dilutions)

• Readout: cell viability (ATP measurement)

• Desired compound profile = Differential cell killing between normal and CLL cells

Chronic Lymphocytic Leukemia

Kills CLL but not normal donor cells

102 CLL Pan-Actives vs. Normal B-Cells

Bench-to-Bedside in Two Years

10/7/2009 In Vitro Activity Demonstrated in Primary CLL Cells

Auranofin Selected as First TLC™ Project

The Learning Collaborative™ Established through Memorandum of

Understanding 6/7/2010

11/5/2010

Cooperative Research and Development Agreement Signed 3/22/2011

8/5/2011 Clearance from FDA to Proceed to Clinical Proof of Concept in CLL

10/7/2011 First CLL Patient Dosed with Auranofin

Auranofin Project Timeline




Disease Foundation,

Academic, DIR

Repurposed



Replacement


Myopathy



Univ. Cancer Center

Disease Foundation,

Academic

Repurposed

Approved Drug

Chronic Lymphocytic

Leukemia











Progressiva




TRND Portfolio

Development of a Targeted New Molecular Entity

Sickle Cell Disease • Principal Collaborator: AesRx, Inc.

• Compound: 5-hydroxymethyl-2-furfural (Aes-103) – binds to sickle hemoglobin and increases oxygen affinity

• Stage of project: Late pre-clinical

• TRND collaborating with AesRx on – Preclinical toxicology

– CMC (Chemistry, Manufacturing, and Quality Control) studies

– Regulatory: interactions with FDA, IND filing

– Proof-of-concept clinical trials

• Other NIH resources collaborating to get drug to clinic – API (Aes-103) manufactured via NIH-RAID program

– NIH Clinical Center Pharmacy collaborating on formulation

– NIH Clinical Center Investigator will perform POC clinical trials

• Greg Kato, NHLBI

Gaps and Timelines - SCD

• Gap analysis: Aes-103 – Potent anti-sickling agent in vitro / in vivo – Orally bioavailable, rapidly permeates RBC membrane – Needs:

• Studies: Preclinical acute/chronic tox, safety, in vitro ADME • CMC: GMP manufacturing, formulation, sufficient amounts for (pre)clinical studies • Regulatory: Complete IND

• Timelines:

– Team / Funding / Gap Analysis / Agreements: 3 months (TRND-AesRx) – Preclinical Studies: 12 months (TRND-CRO) – IND Preparation & Submission: 4 months (TRND-CRO) – Healthy Volunteers Dosed: 1 month (TRND-CRO) – First Patient Dosed: 5 months (TRND-NIH CC)




Disease Foundation,

Academic, DIR

Repurposed



Replacement


Myopathy



Univ. Cancer Center

Disease Foundation,

Academic

Repurposed

Approved Drug

Chronic Lymphocytic

Leukemia











Progressiva




TRND Portfolio

Development of a Known Pathway Intermediate as a Therapeutic

• Principal Collaborators: NHGRI and New Zealand Pharmaceuticals (NZP)

• Compound: N-acetyl-D-mannosamine

– Binds to UDP N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK)

• Stage of project: Late preclinical (Clinical trial hold)

• TRND collaborating on:

– Preclinical toxicology

– CMC (Chemistry, Manufacturing, and Quality Control) studies

– Regulatory: interactions with FDA, IND filing

– Proof-of-concept clinical trials

• Other NIH resources:

– NIH Clinical Center Investigator will perform POC clinical trials and natural history study

• Bill Gahl, NHGRI

• Nuria Carrillo NCATS

– NIH Clinical Center Pharmacy collaborating on formulation

N-acetyl-D-mannosamine (ManNAc)

1 2 4 3 6 5 8 7 10 9 12 11

epimerase kinase

13

M712T D176V

Hereditary Inclusion Body Myopathy

(ManNAc)

Gaps and Timelines - HIBM

• Gap analysis: ManNAc – “Anecdotal” patient experience with orally bioavailable ManNAc – Expect no adverse effects at likely human doses – Project on clinical hold with FDA – Thorough understanding of disease progression – Needs:

• Studies: Preclinical acute/chronic toxicity, genotoxicity, safety, in vitro ADME • CMC: GMP manufacturing, formulation, sufficient amounts for (pre)clinical studies • Regulatory: Complete response to FDA clinical hold • Natural History Study

• Timelines:

– Team / Funding / Gap Analysis / Agreements: 5 months (TRND-NHGRI) – Preclinical Studies: 12 months (TRND-CRO) – Regulatory Support: 9 months [ongoing] (TRND-CRO) – Filed complete response to clinical hold 7/27/2012




Disease Foundation,

Academic, DIR

Repurposed



Replacement


Myopathy



Univ. Cancer Center

Disease Foundation,

Academic

Repurposed

Approved Drug

Chronic Lymphocytic

Leukemia











Progressiva




TRND Portfolio

Pathway Derived Repurposing: Changing the Route of Administration of an Approved Drug

Repurposing an Approved Drug by Changing the Route of Administration

Pulmonary Alveolar Proteinosis

• Principal Collaborator: Bruce Trapnell

(Cincinnati Children’s Hospital)

• Clinical Manifestation:

– Accumulation of surfactant in pulmonary alveoli

– Impaired gas exchange

– Hypoxemic respiratory failure

• Current Treatment

– Whole lung lavage under general anesthesia

– Requires 15 L saline

– Technically challenging, invasive, pediatric safety concerns

• Compound: GM-CSF

– Required for terminal differentiation and maturation of alveolar macrophages

– Approved in IV form (Sargromostim) for

• Myeloid reconstitution after bone marrow transplant

• Neutropenia induced by chemotherapy in AML

• Path Forward / Gaps:

– Significant human experience with GM-CSF via IV

• Initial studies indicate high doses of GM-CSF by IV or SC are needed to have impact in the lung

– Ex-US studies of inhaled GM-CSF indicate efficacy in autoimmune PAP

– To begin US study:

• Need inhaled NHP toxicology data

N Engl J Med 2007; 357:e21

Eur J Radiol 2011, May 26; http://dx.doi.org/10.1016/j.ejrad.2011.05.005

PAP infiltration 4 days post lavage

Whole Lung Lavage Fluid

Overview

• What is TRND?




• Questions

TRND is Different

Usual NIH Mechanism

Apply, Grants.Gov

Review, NIH CSR $

Funding Opportunity

Announcement

Funding Decision

Apply, Proposal CENTRAL

Review, TRND Panel

Collaborate with TRND

Milestone-Driven, In-Kind Research

Support

Solicitation Select Projects, Form Teams

TRND Mechanism

http://trnd.nih.gov

http://trnd.nih.gov

Preclinical Development/TRND

FDA Collaboration


Repurposing

Lead



Development Target



I II III

Project Entry Point

Repurposing

Unvalidated target

Validated target

Lead compound


candidate


candidate

Assay Dev

Target assay

TRND Project Entree

• Small Molecule and Biologic modalities accepted

• Projects enter TRND from lead optimization to IND filing • After HTS and other lead finding and validation work is completed

Application

Application

Application Documents

TRND Concept Application (5-page Template)

• Background

• Therapeutic Hypothesis

• Current State of Project

• Proposed Development Strategy

• Justification

• Timeline and Milestones

• Appendices

Application Documents (cont’d)

Appendices

• Compound Data Tables

• References

• Public Abstract

• Intellectual Property (IP) Information

• Key Investigators Biosketch

Application Documents (cont’d)

Appendices

• Compound Data Tables

• References

• Public Abstract

• Intellectual Property (IP) Information

• Key Investigators Biosketch

https://proposalcentral.altum.com/default.asp?GMID=80

ProposalCENTRAL



Overview

• What is TRND?




• Questions

TRND Program Evaluation: Key

Criteria (by weight)

• Target and therapeutic validation (30%)

• Strength of current data package (30%)

• Feasibility to reach First in Human (20%)

• Medical impact relative to current Standard of Care (10%)

• Likelihood of external adoption (10%)

Criteria: Strength of Data Package

• Medicinal Chemistry

• ADME

• PK/PD

• Toxicology

• In vivo models

• Secondary and tertiary assays

• Formulation

• Chemical Manufacturing and Controls (CMC) – Small molecules

• Expression/Purification – Biologics

Criteria: Feasibility to FIH

– Animal models to establish efficacy

– Clinical translation pathway, established clinical endpoints

– Patient population, well defined with registries

– Biobanks

– Natural history studies complete

– Once FDA approved, projected

ability to treat disease

40

Compound Efficacy Profile

(Conditions in parentheses)

In Vitro Biology Units Value & Class Goal

Activity

(Assay 1) - IC50 nM # < 1000

(Assay 1) - Ki nM # < 1000

(Assay 2) - IC50 nM # < 1000

(Assay 2) – Ki nM # < 1000

Selectivity

(Assay 1) - IC50 / Fold selectivity nM #, # > 100

In Vivo Biology Units Value & Class Goal (Species, dose, route) – MED nM #

(Species, dose, route) - MED nM # (Species, dose, route) - MED nM #

PK Properties Units Dose (mpk),

Route,

Species

Dose (mpk),

Route,

Species

Goal t1/2 hr # # > 3

AUC0-∞, total,

unbound hr*ng/mL #, # #, # > 500 (PO)

CL mL/min/kg # # < 25% HBF

Cmax, total, unbound ng/mL (nM) #, # #, #

Tmax hr # #

Vd L/kg # #

F % # # > 20%

Other Biology Units Value & Class Goal #

#

• Compound Profiling and Efficacy Tables in Appendix

• Enter the data that you have

• Full data tables not required to be successful

Overview

• What is TRND?




• Questions

New Project Selection

• Solicitation Opens: August 1st

• Solicitation Closes: September 30th, 11:59 pm

• Non-Responsive Applications Notified: Early October

• Initial Feedback: Mid December

• TRND Final Decisions: Late March

TRND Solicitation: Important Dates 2012 Cycle

How TRND Manages Collaborative Development Projects

TRND Management of: Project Plan, Milestones,

Ongoing Review

Implement Joint Project Plan

Project Team: TRND + Partner + Academics

+ Sub-Contractors

Collaboration Agreement

TRND OVERSIGHT

Trans-NIH Advisory

Group

Joint Research

Committee

Intellectual Property

• Collaborators retain background IP, generated prior to initiation of TRND collaboration

• Potential for development of multi-party IP depends on stage at which project enters into TRND program

• Inventorship of new IP created during TRND collaboration will be determined according to U.S. patent law

Introduction to NIH R&D Agreements

Goal for NIH is:

• To maximize innovation by facilitating industry and university collaborations and sharing of scientific/technical knowledge.

• Foster the successful commercialization of new therapeutics to treat rare and neglected diseases

Available NIH agreement are:

• MTA and CDAs - External assets and know-how can be “brought in” through these agreements.

• Research collaboration agreement (RCA)

• Collaborative Research & Development Agreement (CRADA)

• Clinical research agreements

• Standard Forms / Model Agreements can be found by searching “Model Agreements” on the TRND / NCATS website, or at:

•http://www.ncats.nih.gov/about/org/divs-offices/strategic-alliances/model-agreements.html

47

http://www.ncats.nih.gov/about/org/divs-offices/strategic-alliances/model-agreements.html









Probe Development Preclinical Development/TRND

NIH-RAID

Clinical

FDA Collaboration

Systems Toxicology

RNAi


Repurposing

Lead



Development Target



I II III

Project Entry Point

Deliverables

DPI

Repurposing

Unvalidated target

Validated target

Lead compound


candidate


candidate

Genome-wide RNAi systems biology data

Chemical genomics

systems biology data

Small molecule and siRNA research probes

More efficient/faster/cheaper translation and therapeutic development

Leads for therapeutic

development

Predictive in vitro toxicology profiles

Approved drugs effective for new

indications

New drugs for untreatable diseases

Novel clinical trial designs

Drugs suitable for adoption for further

development

Assay Dev

Assay Dev

NCATS Division of Preclinical Innovation: An Integrated Pipeline

Target assay

NCATS DPI Staff

Lab Operations Automation and Cmd Mgt,

ChemistryAssay Development and Biology

Informatics

Scientific and Admin

Management

http://images.google.com/imgres?imgurl=http://www.nb.cmha.ca/data/1/rec_imgs/1091_GSK 5Colour Jpeg.jpg&imgrefurl=http://www.nb.cmha.ca/bins/content_page.asp?cid=284-1007-1634&lang=2&h=645&w=1908&sz=79&hl=en&start=4&tbnid=XEqmT63cOaptcM:&tbnh=51&tbnw=150&prev=/images?q=gsk&svnum=10&hl=en&rls=GGIH,GGIH:2007-02,GGIH:en

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http://www.pfizer.com/home/

http://images.google.com/imgres?imgurl=http://www.pac3.org/images/MerckLogo.GIF&imgrefurl=http://www.pac3.org/events/summit/03302007summit.htm&h=341&w=1061&sz=19&hl=en&start=1&tbnid=zKPC4aMg81pdOM:&tbnh=48&tbnw=150&prev=/images?q=merck&svnum=10&hl=en&rls=GGIH,GGIH:2007-02,GGIH:en

http://www.amphoracorp.com/default.aspx

http://www.northropgrumman.com/index.html

http://www.bdbiosciences.com/

http://www.lilly.com/


Further Information

John McKew, Ph.D.

Branch Chief, TRND Head of Chemistry, DPI

Nora Yang, Ph.D., M.B.A.

Director, Strategy and Program Operations, TRND

Online: http://trnd.nih.gov Email: [email protected]

Andre Pilon, Ph.D.

Program Analyst, TRND

Overview

• What is TRND?




• Questions